The long range objectives are to examine the structure and products of neurobiologically-important genes. The focus is to examine genes encoding the cyclic nucleotide phosphodiesterases (PDEs), to understand the structure of these enzymes and to elucidate their neurobiological functions. Continued studies of the Drosophila dunce+ gene are proposed; this gene participates in memory processes of learned behavior and in female fertility. Recent studies of dunce+ cDNA clones have unambiguously assigned a cAMP PDE function to this gene, because its predicted translation product shares extensive homology with a bovine cyclic nucleotide PDE. In addition, a potential neuropeptide-encoding function is suggested by the homology of the dunce+ translation product to Aplysia egg-laying hormone (ELH). Certain structural and biological considerations make the hypothesis that dunce+ encodes both PDE and ELH functions tenable. The proposed studies will include further examination of the structure of the gene, especially near the 5' end. Flies will be transformed with the complete gene in order to define the minimum sequence required for normal activity, and to overexpress the product(s) of the dunce gene. The biological consequences of increased PDE activity and the potential ELH function will be assessed. Anti-peptide antibodies will be made to portions of the dunce+ translation product including the ELH homology, and these will be used as probes to search for an ELH molecule in fly homogenates. The PDE will be purified and this molecule subjected to partial sequence analysis to understand its structure in vivo. Genome sequences homologous to dunce+ in the rat will be studied, and cDNA clones for these isolated to address questions of gene evolution and protein structure, and to potentially determine whether dunce+-like sequences participate in memory processes in mammals. In addition, the gene for another form of cyclic nucleotide PDE, a calcium:calmodulin-dependent PDE, will be isolated from Drosophila and analyzed to help determine whether this enzyme performs important neurobiological roles as does its sister enzyme, the cAMP PDE of dunce+.